The hippocampal formation is an important component of the brain's medial temporal lobe memory system that allows individuals to encode information about episodes of their lives. Much is known about the network of connections that mediates this function in the mature brain. The dentate gyrus, hippocampus and subiculum receive major inputs from the entorhinal cortex via the perforant path. This is likely the raw material from which episodic memories are made. The entorhinal cortex, in turn, has prominent bidirectional connections with several polysensory cortical regions prominently including the perirhinal, parahippocampal and retrosplenial cortices. This neuroanatomy suggests that the hippocampus makes memories mainly using highly processed, multisensory information and likely stores the encoded information in these very same polysensory cortices. There are remarkably few studies of the development of the hippocampal formation in any species, and even fewer in man and in the nonhuman primate. If this information were available, it might provide some insights into why humans are typically unable to remember episodes of their lives prior to three years of age. Entorhinal projections to the human hippocampal fields and subiculum are observed by 19-22 weeks of gestation (Hevner and Kinney, 1996) though there is no available evidence concerning when the mature pattern of fiber projections is developed. During the previous funding period, we demonstrated that an essentially adult pattern of perforant path connections is established in the newborn rhesus monkey. We now propose to extend these studies to the fetal brain to determine when the perforant path is first established in the rhesus monkey and when and how it matures to an adult pattern. We are also now prepared to start an analysis of the developing human hippocampal formation for which there is only very limited information. We propose to extend our nonhuman primate studies to the human brain by carrying out quantitative, stereological analyses of cell number and volume increases of the hippocampal formation throughout the lifespan. Finally, we propose to initiate a new program of structure/function analyses of the postnatally developing hippocampal formation in the rhesus monkey by carrying out a longitudinal magnetic resonance imaging (MRI) analysis of the brains of developing rhesus monkeys followed by behavioral assessments of their memory capacity. We had previously found that the total volume of the hippocampus in typically developing children ranges in size from 4.5 cm3 to 6.5 cm3 and that the size of the hippocampus in these children was strongly correlated with their IQ. This would suggest that a larger hippocampus predicts better memory function. But, is one born with a larger hippocampus or does the hippocampus benefit from an enriched upbringing? Also, if an individual hippocampus is larger, is this because there are more neurons, or neurons that have more elaborate connections? We will explore these nature/nurture questions using the rhesus monkey model. PUBLIC HEALTH RELEVANCE: The hippocampus is part of the brain's memory system that allows individuals to remember episodes of their lives. There is very little information about how the hippocampus develops. But, it is clear that it is vulnerable to a variety of traumas that occur during fetal life, during birth and shortly after birth. These studies will provide new information on how the hippocampus develops in humans and in rhesus monkeys. The new information will have implications for normal cognitive function through the lifespan and for disorders such as epilepsy, learning disabilities and the vulnerability to Alzheimer's disease.